β-Amyloid (Aβ) Oligomers Impair Brain-derived Neurotrophic Factor Retrograde Trafficking by Down-regulating Ubiquitin C-terminal Hydrolase, UCH-L1

Abstract

Background: Axonal transport deficits are part of Alzheimer disease (AD) pathobiology. Results: ␤-Amyloid (A␤) impairs BDNF-dependent retrograde signaling, which is rescued by increasing cellular UCH-L1 levels. Conclusion: In AD, A␤ impairs neurotrophin-mediated retrograde signaling by disrupting ubiquitin homeostasis. Significance: Elucidating the mechanism by which A␤ causes transport deficits that compromise synaptic plasticity and neuronal survival is crucial for discovering novel therapeutics to reverse cognitive deficits in AD.

Computable cause‐and‐effect models of healthy and Alzheimer's disease states and their mechanistic differential analysis

“…This blockade leads to the repression of neuron survival, differentiation, and growth, so that abnormal APP processing and amyloidbeta production has been experimentally shown to attenuate BDNF-NTRK2 signaling [10]. UCHL1 activity is repressed by amyloid-beta, which in turn impairs BDNF-NTRK2-mediated downstream signaling, leading to diminished synaptic plasticity and neuronal survival [11]. Our BEL models also shed light on a second pathophysiology mechanism of two other proteins involved in neurotrophin signaling: NGFR and NGF.…”

“…In the normal state, the NGF protein binds to NGFR resulting in NGFR polyubiquitination. Ubiquitinated NGFR binds to inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta (IKBKB) and activates nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NFKB1), which promotes neuronal cell survival [11]. In the disease state, amyloid beta peptides competitively bind to the NGFR and inhibit the binding of NGF, resulting in increased cell death [13,14].…”

Differential effect of amyloid beta peptides on mitochondrial axonal trafficking depends on their state of aggregation and binding to the plasma membrane

“…However, while some studies demonstrated that axonal trafficking is mostly affected by soluble Aβ oligomers, others suggest that fibrils are the most detrimental species (Decker et al, 2010; Meyer-Luehmann et al, 2008; Pigino et al, 2009; Poon et al, 2011; Poon et al, 2013; Ramser et al, 2013; Wang et al, 2010). Moreover, different methods adopted by individual laboratories for Aβ peptide preparation, significant range of doses utilized in the experiments, the duration of treatment, and the variety of cellular models and methods to monitor axonal motility make a direct comparison and the result interpretation difficult.…”

Failure of Ubiquitin Proteasome System: Risk for Neurodegenerative Diseases

“…An inhibition of UCH-L1 influences memory functions [79]. Recently, a study by Poon et al [80] indicated that UCH-L1 is important for regulating neurotrophin receptor sorting to signaling endosomes and supporting retrograde transport. These results suggest that Aβ can downregulate UCH-L1 in the AD brain, which in turn impairs BDNF/TrkB-mediated retrograde signaling and compromises synaptic plasticity and neuronal survival.…”